Carcinogenesis as a consequence of polycyclic hydrocarbon administration may represent at least in part the end result of an imbalance among several genetically-determined processes occurring within a tissue--activation to epoxides, detoxification of the latter to diols, interaction with macromolecules, i.e., RNA, DNA or protein, conjugation of epoxides with glutathione and the extent of the DNA repair process. Furthermore, the metabolism of polycyclic hydrocarbons is markedly elevatd by administration of a number of pollutants, i.e., environmentally-influenced, and the extent of the induction appears also genetically-determined. The objectives of the proposal are to ascertain 1) the nature of metabolites of 3,4 Benzpyrene (BP) and 3-methylcholanthrene (3MC) produced by microsomal preparations of mouse and rat liver, lung and skin, using high pressure liquid chromatographic techniques, 2) the specific activities of epoxide hydrase, epoxidase (after development of an assay), glutathione S-epoxide transferase in these tissues, 3) the variation in the nature of metabolites and in the levels of these enzymes as a result of prior exposure (administration) of 'inducers', e.g., 3MC, phenobarbital, beta-naphthoflavone, pregnenolone 16-alpha carbonitrile, 4) the extent of alkylation of DNA by labelled polycyclic hydrocarbons using in vitro microsomal preparations obtained from tissues of control and 'induced' rats and, 5) the skin tumorigenicity (in mice) of 3MC as influenced by blockade of epoxide hydrase and 'inducers'. In addition, we wish to obtain some information relative to the range of specific activities of epoxidase, epoxide hydrase, aryl hydrocarbon hydroxylase and the glutathione S-epoxide transferase in human tissues, i.e., foreskin; the magnitude of induction of these enzymes after exposure to 3MC and other 'inducers', and the range of the extent of alkylation of DNA by labelled polycyclic hydrocarbons using foreskin microsomal preparations in vitro. BIBLIOGRAPHIC REFERENCE: Mukhtar, H. and Bresnick, E. Effects of phenobarbital and 3-methylcholanthrene administration on glutathione S-epoxide transferase activity in rat liver. Biochem. Pharmacol. 25:1081-1084 (1976).